2000 Fiscal Year Final Research Report Summary
Elucidation of the regulatory mechanism for vascular endothelial growth factor (VEGF) expression in diabetic retinopathy
| Project/Area Number |
11694267
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Ophthalmology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
HONDA Yoshihito Kyoto University, Professor, 医学研究科, 教授 (90026930)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAGI Hitoshi Kyoto University, Lecturer, 医学研究科, 講師 (70283596)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Diabetic Retinopathy / neevascularization / Angiopoietin / Angiotensin / pericyte / endothelium / VEGF / ischemia |
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| Research Abstract |
The aim of the study is to elucidate the mechnaism of pathogenesis in early stages of diabetic retinopathy and to develop new strategies to halt the initiation of retinopathy. We mainly focused on the molecular mechanism associated with angiogenic and vasopermeable factors such as vascular endothelial growth factor (VEGF) and angiopoietins (Ang1, 2). Renin-angiotensin system has been shown to be a key player in the development of retinopathy. Our findings demonstrated that All stimulates the vascular abnormalities by increasing VEGF secretion in pericytes and VEGFR2 and Ang2 expression in endothelial cells in retinal microvasculature. In addition, the All-induced response is mediated through AT1 receptor, PKC dependent signaling, and AP1-mediated transcriptional regulation. These molecules could be targets to suppress early events of retinopathy. Ang2 has also been shown to deteriorate endo-periendothelial interaction. Our study revealed that Ang2 is seletively upregulated by VEGF, hypoxia, and diabetes mellitus in vitro or in vivo model. These findings might suggest that the upregulation of the molecule could be one of mechanisms on pericyte loss, which is a significant pathological change as shown to be a trigger to promote vasoproliferative and vasopermeable abnormalities. Since the leukocyte behavior is associated with vasopermeable response in the retina of short-term diabetic animal, we investigated a mechanism and found that PKCβ specific inhibition suppressed leukocyte trapping and invasion. Taken together, inhibition of regulatory mechnism of VEGF and pericyte degeneration such as All, Ang2, and the related-signaling system could be key targets to halt early pathological events of retinopathy
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